Centro Interdipartimentale di Biotecnologie Molecolari "Guido Tarone"
Valeria Poli - PI
Full Professor in Molecular Biology, University of Turin, Italy.
- Somayeh Mirzagahaei, post-doctoral fellow
- Daniele Viavattene, post-doctoral fellow
- Jahnavi Srivasta, PhD student
- Caterina Margheriti, Chiara Verrengia master students
- Andrea Marchetti, Undergraduate student
Research activity
Controlled production of cytokines and growth factors, leading to the activation of specific signalling pathways and to the modulation of gene expression, is essential for life, while aberrant cytokines/growth factors expression, activity or signalling is at the basis of many pathological conditions including chronic inflammation, auto-immunity and oncogenesis. The laboratory has long focused on the axis between the pro-inflammatory cytokine IL-6 and the oncogenic transcription factor STAT3 at the crossroads between inflammation, auto-immunity and cancer, aiming at characterizing STAT3 involvement in both physiological and pathological conditions and making use of both in vitro approaches and genetically modified mouse model (GEMMs).
Tumor biology
In recent years we have demonstrated that constitutively active STAT3 can cooperate with oncogenes such as the HER2/Neu to confer aggressive features to breast tumors and support metastasis formation (Barbieri et al., 2010, Barbieri et al., 2010). We have then shown that aberrantly active STAT3 can regulate energy metabolism and mitochondrial activity and can act as a first hit in tumor transformation, shedding light on its well-known central role in inflammation-induced tumorigenesis (Demaria et al., 2010, Demaria et al, 2012).
More recently, we have demonstrated that STAT3 is essential in mediating the pro-tumorigenic activities of breast Cancer Associated Fibroblasts (CAFs). We identified a STAT3-dependent signature that is conserved in humans, and validated several STAT3-dependent genes encoding for secreted proteins responsible of CAF activities (Avalle et al, 2022).
Ongoing research:
- Genome wide CRISPR Cas screening to identify breast cancer genes responsible of increased drug resistance in response to CAFs.
- Identification of regulatory networks and novel therapeutic targets in breast cancer. We have generated breast cancer gene co-expression networks and identified several Transcription Factor hubs as crucial regulators of breast cancer aggressiveness features . We are now functionally validating our findings and and assessing inhibitory strategies (Savino et al., 2021, 2020, 2019).
- STAT3 anti-apoptotic roles at the ER: We have demonstrated that STAT3 can localize to the ER, where its Serine-phosphorylated form triggers degradation of the calcium channel IP3R3, decreasing calcium release towards the mitochondria and enhancing resistance to apoptosis of basal-like breast cancer cells (Avalle et al., 2019). We are now characterizing the mechanisms mediating STAT3 Serine-phosphorylation at the ER to identify potential novel targets.
- Disentangling the relationships with tumour microenvironment in prostate cancer to better model and target tumour progression. This is a collaborative effort, based on the analysis of CAFs and tumour cells/organoids derived from high risk patient samples.
- Heart auto-immunity. We have shown that STAT3 is both sufficient and necessary to trigger the onset of immune-mediated myocarditis, activating a feed-forward loop involving enhanced IL-6 signalling and complement factors production in the liver (Camporeale et al., 2013), and demonstrated that liver-specific STAT3 or C3 siRNA silencing can both prevent and cure immune-mediated myocarditis (Avalle et al., 2020). Current research aims at repurposing already approved inhibitors of STAT3 activation such as JAK kinase inhibitors, and assessing the value of dosing complement activation to predict disease progression in a cohort of patients.
2014-2023 Truus and Gerrit van Riemsdijk Foundation, Vaduz, Liechtenstein. Role of Stat3 in tumorigenesis (Donation). PI, 150,000 €
Piedmont Region F.E.S.R. 2014-2020 DEFLeCT: Digital tEchnology For Lung Cancer Treatment, co-PI, 70,000 €.
MUR PRIN 2017 019-2021, “Prostate cancer: disentangling the relationships within the tumour microenvironment to better model and target tumour progression”. PI and Project co-ordinator, 216,000 €.
AIRC IG 24851 2021-2025, “Exploiting network analysis to unravel breast cancer molecular features and identify novel targets”, PI, 684,000 €.
Health Ministry Finalized Research 2019 2021-2023, “Biopsy-proven myocarditis: genetic background, predictors of dismal prognosis and of response to immunosuppressive therapy and preclinical evaluation of innovative immunomodulatory therapies”. Co-applicant, 90,000 €.
MUR PRIN 2022 2023-2025, DEsiRE-Pre-clinical development of siRNA-based non-targeted and targeted approaches to interfere with STAT3 activity and CAF-tumor cross-talk in breast cancer. PI and Project co-ordinator, 203,329 €.
Savino A, De Marzo N, Provero P, Poli V. Meta-Analysis of Microdissected Breast Tumors Reveals Genes Regulated in the Stroma but Hidden in Bulk Analysis. Cancers 2021, 13(13):3371. doi: 10.3390/cancers13133371.
Avalle L, Raggi L, Monteleone E, Savino A, Viavattene D, Statello L, Camperi A, Aversano Stabile S, Salemme V, De Marzo N, Marino F, Guglielmi C, Lobascio A1, Zanini C, Forni M, Incarnato D, Defilippi P, Oliviero S, Poli V. STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion by Cancer Associated Fibroblasts, 2022 Oncogene, Online ahead of print, doi: 10.1038/s41388-021-02172-y
Avalle L., Marino F., Camporeale A., Guglielmi C., Viavattene D., Bandini S., Conti L., Cimino J., Forni M., Zanini C., Ghigo A., Bogorad R.L., Cavallo F., Provero P., Koteliansky V. and Poli V. Liver-specific siRNA-mediated Stat3 or C3 knock-down improves the outcome of experimental autoimmune myocarditis, Mol Ther Methods Clin Dev. 2020, 18:62-78. https://doi.org/10.1016/j.omtm.2020.05.023
D'Alise AM, Leoni G, Cotugno G, Troise F, Langone F, Fichera I, De Lucia M, Avalle L, Vitale R, Leuzzi A, Bignone V, Di Matteo E, Tucci FG, Poli V, Lahm A, Catanese MT, Folgori A, Colloca S, Nicosia A, Scarselli E. Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade. Nat Commun. 2019, 10:2688. doi: 10.1038/s41467-019-10594-2.
Avalle L, Camporeale A, Morciano G, Caroccia N, Ghetti E, Orecchia V, Viavattene D, Giorgi C, Pinton P, Poli V. STAT3 localizes to the ER, acting as a gatekeeper for ER-mitochondrion Ca2+ fluxes and apoptotic responses. (2018) Cell Death Differ. 2019, 26(5):932-942. doi: 10.1038/s41418-018-0171-y.
Avalle L, Incarnato D, Savino A, Gai M, Marino F, Pensa S, Barbieri I, Stadler MB, Provero P, Oliviero S, Poli V. MicroRNAs-143 and -145 induce epithelial to mesenchymal transition and modulate the expression of junction proteins. (2017) Cell Death Differ., 24(10):1750-1760. doi:10.1038/cdd.2017.103. doi: 10.1038/cdd.2017.103. PMID: 28644441.
Laklai H, Miroshnikova YA, Pickup MW, Collisson E, Kim GE, Barrett AS, Hill RC, Lakins JN, Schlaepfer DD, Mouw JK, LeBleu VS, Novitskiy SV, Johansen JS, Poli V, Kalluri R, Iacobuzio-Donahue CA, Wood LD, Hebrok M, Hansen K, Moses HL and Weaver VW. Genotype tunes PDAC tension to induce matricellular-fibrosis and tumor aggression. (2016) Nature Medicine 22, 497–505, doi:10.1038/nm.4082.
Camporeale A, Marino F, Papageorgiou A, Carai P, Fornero S, Fletcher S, Page BDG, Gunning P, Forni M, Chiarle R, Morello M, Jensen O, Levi R, Heymans S, Poli V. STAT3 activity is necessary and sufficient for the development of immune-mediated myocarditis in mice and promotes progression to dilated cardiomyopathy. (2013) EMBO Mol. Medicine 5: 572–590, DOI: 10.1002/emmm.201201876.
Demaria M, Misale S, Giorgi C, Miano V, Camporeale A, Campisi J, Pinton P and Poli V. STAT3 can serve as a hit in the process of malignant transformation of primary cells. 2012, Cell Death and Differentiation 19: 1390-1397.
Kreuzaler PA, Staniszewska AD, Li W, Omidvar N, Kedjouar B, Turkson J, Poli V, Flavell RA, Clarkson RWE, and Watson CJ. Stat3 controls lysosomal mediated cell death in vivo. (2011) Nature Cell Biology 13:303-309.
